The prenatal use of agmatine prevents social behavior deficits in VPA-exposed mice by activating the ERK/CREB/BDNF signaling pathway.

BACKGROUND: According to reports, prenatal exposure to valproic acid can induce autism spectrum disorder (ASD)-like symptoms in both humans and rodents. However, the exact cause and therapeutic method of ASD is not fully understood. Agmatine (AGM) is known for its neuroprotective effects, and this study aims to explore whether giving agmatine hydrochloride before birth can prevent autism-like behaviors in mouse offspring exposed prenatally to valproic acid. METHODS: In this study, we investigated the effects of AGM prenatally on valproate (VPA)-exposed mice. We established a mouse model of ASD by prenatally administering VPA. From birth to weaning, we evaluated mouse behavior using the marble burying test, open-field test, and three-chamber social interaction test on male offspring. RESULTS: The results showed prenatal use of AGM relieved anxiety and hyperactivity behaviors as well as ameliorated sociability of VPA-exposed mice in the marble burying test, open-field test, and three-chamber social interaction test, and this protective effect might be attributed to the activation of the ERK/CREB/BDNF signaling pathway. CONCLUSION: Therefore, AGM can effectively reduce the likelihood of offspring developing autism to a certain extent when exposed to VPA during pregnancy, serving as a potential therapeutic drug.

Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review.

BACKGROUND AND OBJECTIVES: To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring. METHODS: Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings. RESULTS: Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures. DISCUSSION: The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.

Exposure to Environmental Pesticides and the Risk of Autism Spectrum Disorders: A Population-Based Case-Control Study.

Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in communication, social interactions, and repetitive behaviors. Although the factors that influence the development of this condition are unknown, certain chemical compounds such as pesticides have been proposed as possible contributors. Due to the lack of an established causal link between pesticide exposure and ASD, this study aimed to evaluate this potential association. Materials and Methods: A case-control study was carried out to ascertain the prevalence and risk associated with ASD in relation to pesticide exposure over a 21-year study period (2000-2021). Results: We included 2821 individuals diagnosed with ASD residing in areas of both high and low pesticide exposure in southern Spain. There was a rise in the ASD prevalence rate in regions with elevated pesticide use when compared to regions with low use [odds ratio (OR): 1.34, 95% confidence interval (CI), (1.24-1.44)]. Notably, men had the highest likelihood, with an OR: 1.42, 95% CI, (1.30-1.55). Furthermore, after performing multiple binary logistic regression adjusted for age, sex, and geographical area, males exhibited a higher likelihood compared to females [OR: 2.41, 95% CI, (2.21-2.62)]. Conclusions: Overall, this research suggests a connection between heightened environmental pesticide exposure due to increased agricultural use and autism.

Early-life exposure to PM2.5 leads to ASD-like phenotype in male offspring rats through activation of PI3K-AKT signaling pathway.

Previous studies have shown that early-life exposure to fine particulate matter (PM2.5) is associated with an increasing risk of autism spectrum disorder (ASD), however, the specific sensitive period of ASD is unknown. Here, a model of dynamic whole-body concentrated PM2.5 exposure in pre- and early-postnatal male offspring rats (MORs) was established. And we found that early postnatal PM2.5 exposed rats showed more typical ASD behavioral characteristics than maternal pregnancy exposure rats, including poor social interaction, novelty avoidance and anxiety disorder. And more severe oxidative stress and inflammatory responses were observed in early postnatal PM2.5 exposed rats. Moreover, the expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN) was down-regulated and the ratios of p-PI3K/PI3K and p-AKT/AKT were up-regulated in early postnatal PM2.5 exposed rats. This study suggests that early postnatal exposure to PM2.5 is more susceptible to ASD-like phenotype in offspring than maternal pregnancy exposure and the activation of PI3K-AKT signaling pathway may represent underlying mechanisms.

Associations between brake and tire wear-related PM2.5 metal components, particulate oxidative stress potential, and autism spectrum disorder in Southern California.

BACKGROUND: Air pollution is a global health concern, with fine particulate matter (PM2.5) constituents posing potential risks to human health, including children's neurodevelopment. Here we investigated associations between exposure during pregnancy and infancy to specific traffic-related PM2.5 components with Autism Spectrum Disorder (ASD) diagnosis. METHODS: For exposure assessment, we estimated PM2.5 components related to traffic exposure (Barium [Ba] as a marker of brake dust and Zinc [Zn] as a tire wear marker, Black Carbon [BC]) and oxidative stress potential (OSP) markers (Hydroxyl Radical [OPOH] formation, Dithiothreitol activity [OPDTT], reactive oxygen species [ROS]) modeled with land use regression with co-kriging based on an intensive air monitoring campaign. We assigned exposures to a cohort of 444,651 children born in Southern California between 2016 and 2019, among whom 11,466 ASD cases were diagnosed between 2018 and 2022, Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained with logistic regression for single pollutant and PM2.5 mass co-adjusted models, also adjusting for sociodemographic characteristics. RESULTS: Among PM2.5 components, we found the strongest positive association with ASD for our brake wear marker Ba (ORper IQR = 1.29, 95 % CI: 1.24, 1.34). This was followed by an increased risk for all PM2.5 oxidative stress potential markers; the strongest association was with ROS formation (ORper IQR = 1.22, 95 % CI: 1.18, 1.25). PM2.5 mass was linked to ASD in Hispanic and Black children, but not White children, while traffic-related PM2.5 and OSP markers increased ASD risk across all groups. In neighborhoods with the lowest socioeconomic status (SES), associations with ASD were stronger for all examined pollutants compared to higher SES areas. CONCLUSIONS: Our findings suggest that brake wear-related PM2.5 and PM2.5 OSP are associated with ASD diagnosis in Southern California. These results suggest that strategies aimed at reducing the public health impacts of PM2.5 need to consider specific sources.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Agmatine ameliorates valproic acid-induced depletion of parvalbumin-positive neuron.

Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with unknown etiology. Dysfunction of several brain areas including the prefrontal cortex (PFC), hippocampus, and cerebellum is involved in cognitive and behavioral deficits associated with ASD. Several studies have reported a reduction in the number of parvalbumin-immunoreactive (PV+) neurons in brain areas of ASD patients and animal models such as a shank mutant mouse model and rodents receiving fetal valproic acid (VPA) administration. Developing therapeutic interventions that restore PV interneurons can be the future therapeutic approach to ASD. The present study examined the possible effect of agmatine (AG), an endogenous NMDA antagonist, on the number of PV+ neurons in a VPA animal model of autism. The therapeutic effects of AG in ameliorating ASD-like behaviors were previously reported in VPA rats. AG was gavaged at dosages of 0.001, 0.01, and 0.1 mg/kg from gestational day (GD) 6.5 to 18.5, and the number of PV interneurons was analyzed by immunohistochemistry in the 1-month-old rats. Prenatal VPA (GD 12.5) or AG led to a decrease of PV neurons in the PFC, Cornu ammonia (CA1), and molecular layers (MLs) of the cerebellum. However, exposure to AG restored the PV population induced by VPA. AG may modify underlying neuronal mechanisms resulting in the increased survival or restoration of the PV population.

Benefits of bone marrow mesenchymal stem cells compared to their conditioned medium in valproic acid-induced autism in rats.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, a limited range of activities, and deficiencies in social communications. Bone marrow mesenchymal stem cells (BM-MSCs), which secrete factors that stimulate surrounding microenvironment, and BM-MSCs conditioned medium (BM-MSCs-CM), which contains cell-secreted products, have been speculated to hold potential as a therapy for ASD. This study aimed to compare the therapeutic effects of BM-MSCs and BM-MSCs-CM on behavioral and microglial changes in an animal model of autism induced by valproic acid (VPA). METHODS AND RESULTS: Pregnant Wistar rats were administered by VPA at a dose of 600 mg/kg at 12.5 days post-conception. After birth, male pups were included in the study. At 6 weeks of age, one group of rats received intranasal administration of BM-MSCs, while another group received BM-MSCs-CM. The rats were allowed to recover for 2 weeks. Behavioral tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry were performed. Both BM-MSCs and BM-MSCs-CM administration significantly improved some behavioral deficits. Furthermore, these treatments notably reduced Iba-1 marker associated with microgliosis. Additionally, there was a significant reduction in the expression of pro-inflammatory cytokines IL-1ß and IL-6, and an increase in the levels of the anti-inflammatory cytokine IL-10 in rats administered by BM-MSCs and BM-MSCs-CM. CONCLUSIONS: Post-developmental administration of BM-MSCs and BM-MSCs-CM can ameliorate prenatal neurodevelopmental deficits, restore cognitive and social behaviors, and modulate microglial and inflammatory markers. Results indicated that the improvement rate was higher in the BM-MSCs group than BM-MSCs-CM group.

The emerging role of α7nAChRs/caspase-3/Nrf-2 signaling pathway in citicoline improved autistic behavior induced by thimerosal in mice.

AIMS: Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD. MATERIALS AND METHODS: The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 µg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers. KEY FINDINGS: Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1ß). The drug also increased the brain GPx activity. SIGNIFICANCE: Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

Ameliorating effect of pioglitazone on prenatal valproic acid-induced behavioral and neurobiological abnormalities in autism spectrum disorder in rats.

Autism spectrum disorder (ASD) is a neurodevelopment disorder that mainly arises due to abnormalities in different brain regions, resulting in behavioral deficits. Besides its diverse phenotypical features, ASD is associated with complex and varied etiology, presenting challenges in understanding its precise neuro-pathophysiology. Pioglitazone was reported to have a fundamental role in neuroprotection in various other neurological disorders. The present study aimed to investigate the therapeutic potential of pioglitazone in the prenatal valproic acid (VPA)-model of ASD in Wistar rats. Pregnant female Wistar rats received VPA on Embryonic day (E.D12.5) to induce autistic-like-behavioral and neurobiological alterations in their offspring. VPA-exposed rats presented core behavioral symptoms of ASD such as deficits in social interaction, poor spatial and learning behavior, increased anxiety, locomotory and repetitive activity, and decreased exploratory activity. Apart from these, VPA exposure also stimulated neurochemical and histopathological neurodegeneration in various brain regions. We administered three different doses of pioglitazone i.e., 2.5, 5, and 10 mg/kg in rats to assess various parameters. Of all the doses, our study highlighted that 10 mg/kg pioglitazone efficiently attenuated the autistic symptoms along with other neurochemical alterations such as oxidative stress, neuroinflammation, and apoptosis. Moreover, pioglitazone significantly attenuated the neurodegeneration by restoring the neuronal loss in the hippocampus and cerebellum. Taken together, our study suggests that pioglitazone exhibits therapeutic potential in alleviating behavioral abnormalities induced by prenatal VPA exposure in rats. However, further research is needed to fully understand and establish pioglitazone's effectiveness in treating ASD.

Ligustilide inhibits Purkinje cell ferritinophagy via the ULK1/NCOA4 pathway to attenuate valproic acid-induced autistic features.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder in which social impairment is the core symptom. Presently, there are no definitive medications to cure core symptoms of ASD, and most therapeutic strategies ameliorate ASD symptoms. Treatments with proven efficacy in autism are imminent. Ligustilide (LIG), an herbal monomer extracted from Angelica Sinensis and Chuanxiong, is mainly distributed in the cerebellum and widely used in treating neurological disorders. However, there are no studies on its effect on autistic-like phenotypes and its mechanism of action. PURPOSE: Investigate the efficacy and mechanism of LIG in treating ASD using two Valproic acid(VPA)-exposed and BTBR T + Itpr3tf/J (BTBR) mouse models of autism. METHODS: VPA-exposed mice and BTBR mice were given LIG for treatment, and its effect on autistic-like phenotype was detected by behavioral experiments, which included a three-chamber social test. Subsequently, RNA-Sequence(RNA-Seq) of the cerebellum was performed to observe the biological changes to search target pathways. The autophagy and ferroptosis pathways screened were verified by WB(Western Blot) assay, and the cerebellum was stained by immunofluorescence and examined by electron microscopy. To further explore the therapeutic mechanism, ULK1 agonist BL-918 was used to block the therapeutic effect of LIG to verify its target effect. RESULTS: Our work demonstrates that LIG administration from P12-P14 improved autism-related behaviors and motor dysfunction in VPA-exposed mice. Similarly, BTBR mice showed the same improvement. RNA-Seq data identified ULK1 as the target of LIG in regulating ferritinophagy in the cerebellum of VPA-exposed mice, as evidenced by activated autophagy, increased ferritin degradation, iron overload, and lipid peroxidation. We found that VPA exposure-induced ferritinophagy occurred in the Purkinje cells, with enhanced NCOA4 and Lc3B expressions. Notably, the therapeutic effect of LIG disappeared when ULK1 was activated. CONCLUSION: LIG treatment inhibits ferritinophagy in Purkinje cells via the ULK1/NCOA4-dependent pathway. Our study reveals for the first time that LIG treatment ameliorates autism symptoms in VPA-exposed mice by reducing aberrant Purkinje ferritinophagy. At the same time, our study complements the pathogenic mechanisms of autism and introduces new possibilities for its therapeutic options.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Vitamin A ameliorates valproic acid-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive/stereotyped behaviors. Prenatal exposure to valproic acid (VPA) has been reported to induce ASD-like symptoms in human and rodents. However, the etiology and pathogenesis of ASD have not been well elucidated. This study aimed to explore the mechanisms underlying VPA-induced ASD-like behaviors using zebrafish model and investigated whether vitamin A could prevent VPA-induced neurotoxicity. Here, zebrafish embryos were exposed to 0, 25 and 50 µM VPA from 4 to 96 h post fertilization (hpf) and the neurotoxicity was assessed. Our results showed that VPA affected the normal development of zebrafish larvae and induced ASD-like behaviors, including reduced locomotor activity, decreased distance near conspecifics, impaired social interaction and repetitive swimming behaviors. Exposure to VPA decreased the GFP signal in transgenic HuC:egfp zebrafish according to the negative effect of VPA on the expression of neurodevelopmental genes. In addition, VPA enhanced oxidative stress by promoting the production of reactive oxygen species (ROS) and hydrogen peroxide (H2O2) and inhibiting the activity of superoxide dismutase, then triggered apoptosis by upregulation of apoptotic genes. These adverse outcomes were mitigated by vitamin A, suggesting that vitamin A rescued VPA-induced ASD-like symptoms by inhibiting oxidative stress and apoptosis. Overall, this study identified vitamin A as a promising strategy for future therapeutic regulator of VPA-induced ASD-like behaviors.

Lotusine ameliorates propionic acid-induced autism spectrum disorder-like behavior in mice by activating D1 dopamine receptor in medial prefrontal cortex.

Autism spectrum disorder (ASD) is a multifaceted neuropsychiatric condition for which effective drug therapy for core clinical symptoms remains elusive. Lotusine, known for its neuroprotective properties in the treatment of neurological disorders, holds potential in addressing ASD. Nevertheless, its specific efficacy in ASD remains uncertain. This study aims to investigate the therapeutic potential of lotusine in ASD and elucidate the underlying molecular mechanisms. We induced an ASD mouse model through intracerebroventricular-propionic acid (ICV-PPA) injection for 7 days, followed by lotusine administration for 5 days. The efficacy of lotusine was evaluated through a battery of behavioral tests, including the three-chamber social test. The underlying mechanisms of lotusine action in ameliorating ASD-like behavior were investigated in the medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings, western blotting, immunofluorescence staining, molecular docking, and cellular thermal shift assay. The efficacy and mechanisms of lotusine were further validated in vitro. Lotusine effectively alleviated social deficits induced by ICV-PPA injection in mice by counteracting the reduction in miniature excitatory postsynaptic current frequency within the mPFC. Moreover, lotusine enhanced neuronal activity and ameliorated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysfunction in ICV-PPA infusion mice by upregulating c-fos, p-GluA1 Ser 845, and p-GluA1 Ser 831 protein levels within the mPFC. Our findings also suggest that lotusine may exert its effects through modulation of the D1 dopamine receptor (DRD1). Furthermore, the rescuing effects of lotusine were nullified by a DRD1 antagonist in PC12 cells. In summary, our results revealed that lotusine ameliorates ASD-like behavior through targeted modulation of DRD1, ultimately enhancing excitatory synaptic transmission. These findings highlight the potential of lotusine as a nutritional supplement in the treatment of ASD.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats.

BACKGROUND: Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. METHODS: In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. RESULTS: Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. CONCLUSIONS: These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Female mice prenatally exposed to valproic acid exhibit complex and prolonged social behavior deficits.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Perioperative Management and Outcomes in Patients With Autism Spectrum Disorder: A Retrospective Cohort Study.

BACKGROUND: Autism spectrum disorder (ASD) is a neurocognitive disorder characterized by impairments in communication and socialization. There are little data comparing the differences in perioperative outcomes in children with and without ASD. We hypothesized that children with ASD would have higher postoperative pain scores than those without ASD. METHODS: Pediatric patients undergoing ambulatory tonsillectomy/adenoidectomy, ophthalmological surgery, general surgery, and urologic procedures between 2016 and 2021 were included in this retrospective cohort study. ASD patients, defined by International Classification of Diseases-9/10 codes, were compared to controls utilizing inverse probability of treatment weighting based on surgical category/duration, age, sex, race and ethnicity, anesthetizing location, American Society of Anesthesiology physical status, intraoperative opioid dose, and intraoperative dexmedetomidine dose. The primary outcome was the maximum postanesthesia care unit (PACU) pain score, and secondary outcomes included premedication administration, behavior at induction, PACU opioid administration, postoperative vomiting, emergence delirium, and PACU length of stay. RESULTS: Three hundred thirty-five children with ASD and 11,551 non-ASD controls were included. Maximum PACU pain scores in the ASD group were not significantly higher than controls (median, 5; interquartile range [IQR], 0-8; ASD versus median, 5; IQR, 0-8 controls; median difference [95% confidence interval {CI}] of 0 [-1.1 to 1.1]; P = .66). There was no significant difference in the use of premedication (96% ASD versus 95% controls; odds ratio [OR], 1.5; [95% CI, 0.9-2.7]; P = .12), but the ASD cohort had significantly higher odds of receiving an intranasal premedication (4.2% ASD versus 1.2% controls; OR, 3.5 [95% CI, 1.8-6.8]; P < .001) and received ketamine significantly more frequently (0.3% ASD versus <0.1% controls; P < .001). Children with ASD were more likely to have parental (4.9% ASD versus 1.0% controls; OR, 5 [95% CI, 2.1-12]; P < .001) and child life specialist (1.3% ASD versus 0.1% controls; OR, 9.9 [95% CI, 2.3-43]; P < .001) presence at induction, but were more likely to have a difficult induction (11% ASD versus 3.4% controls; OR, 3.42 [95% CI, 1.7-6.7]; P < .001). There were no significant differences in postoperative opioid administration, emergence delirium, vomiting, or PACU length of stay between cohorts. CONCLUSIONS: We found no difference in maximum PACU pain scores in children with ASD compared to a similarly weighted cohort without ASD. Children with ASD had higher odds of a difficult induction despite similar rates of premedication administration, and significantly higher parental and child life specialist presence at induction. These findings highlight the need for future research to develop evidence-based interventions to optimize the perioperative care of this population.

Ultrafine particulate matter exposure during second year of life, but not before, associated with increased risk of autism spectrum disorder in BKMR mixtures model of multiple air pollutants.

Prenatal and early postnatal air pollution exposures have been shown to be associated with autism spectrum disorder (ASD) risk but results regarding specific air pollutants and exposure timing are mixed and no study has investigated the effects of combined exposure to multiple air pollutants using a mixtures approach. We aimed to evaluate prenatal and early life multipollutant mixtures for the drivers of associations of air pollution with ASD. This study examined 484 typically developing (TD) and 660 ASD children from the CHARGE case-control study. Daily air concentrations for NO2, O3, ultrafine (PM0.1), fine (PM0.1-2.5), and coarse (PM2.5-10) particles were predicted from chemical transport models with statistical bias adjustment based on ground-based monitors. Daily averages were calculated for each exposure period (pre-pregnancy, each trimester of pregnancy, first and second year of life) between 2000 and 2016. Air pollution variables were natural log-transformed and then standardized. Individual and joint effects of pollutant exposure with ASD, and potential interactions, were evaluated for each period using hierarchical Bayesian Kernel Machine Regression (BKMR) models, with three groups: PM size fractions (PM0.1, PM0.1-2.5, PM2.5-10), NO2, and O3. In BKMR models, the PM group was associated with ASD in year 2 (group posterior inclusion probability (gPIP) = 0.75), and marginally associated in year 1 (gPIP = 0.497). PM2.5-10 appeared to drive the association (conditional PIP (cPIP) = 0.64) in year 1, while PM0.1 appeared to drive the association in year 2 (cPIP = 0.76), with both showing a moderately strong increased risk. Pre-pregnancy O3 showed a slight J-shaped risk of ASD (gPIP = 0.55). No associations were observed for exposures during pregnancy. Pre-pregnancy O3 and year 2 p.m.0.1 exposures appear to be associated with an increased risk of ASD. Future research should examine ultrafine particulate matter in relation to ASD.